A Study of LGK974 in Patients With Malignancies Dependent on Wnt Ligands

• ClinicalTrials.gov Identifier: NCT01351103
• Recruitment Status: Active, not recruiting
• First Posted: May 10, 2011
• Last Update Posted: March 15, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: May 4, 2011
• First Posted Date: May 10, 2011
• Last Update Posted Date: March 15, 2024
• Actual Study Start Date: December 1, 2011
• Actual Primary Completion Date: June 14, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 24, 2017)

Maximum Tolerated Dose or Recommended Dose for Expansion of LGK974 as a single agent or in combination with PDR001 in patients treated [ Time Frame: 34 months ]

Determine the Maximum Tolerated Dose (MTD) or Recommended Dose for Expansion (RDE) of LGK974 as a single agent and in combination with PDR001 when administered orally to adult patients with malignancies dependent on Wnt ligands.

• Original Primary Outcome Measures (submitted: May 9, 2011): Maximum Tolerated Dose of LGK974 in patients treated daily [ Time Frame: 12 months ]

Current Secondary Outcome Measures (submitted: September 14, 2021)

• Type and category of study drug related adverse events (AE) [ Time Frame: 61 months ]
  The incidence of treatment-emergent adverse events (new or worsening from baseline) will be summarized by primary system organ class, severity based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, type of AE, relationship to study drug by dose group.
• Absorption and plasma concentrations of LGK974 [ Time Frame: 61 months ]
  Evaluate pharmacokinetic (PK) parameters such as AUClast, AUCtau, Cmax, the apparent elimination T1/2 and Racc for LGK974 and its pharmacologically metabolite.
• PD related to the Wnt pathway [ Time Frame: 61 months ]
  Assessing percent change from baseline to post-treatment of PD related to the Wnt pathway.
• Overall response rate of tumor [ Time Frame: 61 months ]
  Patients with an Overall Response Rate(ORR), complete response (CR) or partial response (PR) rate and duration of response (DOR) assessed by RECIST 1.1 for single agent LGK974 and by RECIST1.1 and irRC for LGK974+PDR001.
• Absorportion and plasma concentrations of PDR001 [ Time Frame: 61 months ]
  Evaluate pharmacokinetic (PK) parameters such as AUClast, AUCtau, Cmax, the apparent elimination T1/2 and Racc for LGK974, its pharmacologically metabolite and PDR001.

Original Secondary Outcome Measures (submitted: May 9, 2011)

• Type and category of study drug related adverse events [ Time Frame: 18 months ]
• Absorption and plasma concentrations of LGK974 [ Time Frame: 18 months ]
• Biomarkers related to the Wnt pathway [ Time Frame: 18 months ]
• Overall response rate of tumor [ Time Frame: 18 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of LGK974 in Patients With Malignancies Dependent on Wnt Ligands
• Official Title: A Phase I, Open-label, Dose Escalation Study of Oral LGK974 in Patients With Malignancies Dependent on Wnt Ligands
• Brief Summary: The primary purpose of this study is to find the recommended dose of LGK974 as a single agent and in combination with PDR001 that can be safely given to adult patients with selected solid malignancies that have progressed despite standard therapy or for which no effective standard therapy exists

Detailed Description

This open-label multicenter phase 1 dose escalation study will be the first to administer LGK974 as a single agent or in combination with PDR001 in humans.

The study will comprise of 2 parts: a dose escalation of LGK974 as a single agent, followed by a safety expansion in specific disease indications; and a dose escalation of LGK974 in combination with PDR001, followed by a safety expansion in cutaneous melanoma.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Pancreatic Cancer
• BRAF Mutant Colorectal Cancer
• Melanoma
• Triple Negative Breast Cancer
• Head and Neck Squamous Cell Cancer
• Cervical Squamous Cell Cancer
• Esophageal Squamous Cell Cancer
• Lung Squamous Cell Cancer

Intervention

• Drug: LGK974
  Other Name: WNT974
• Biological: PDR001

Study Arms

• Experimental: LGK974
  LGK974
  Intervention: Drug: LGK974
• Experimental: LGK974 in combination with PDR001
  LGK in combination with PDR001
  Interventions:

  • Drug: LGK974
  • Biological: PDR001

• Publications *: Rodon J, Argiles G, Connolly RM, Vaishampayan U, de Jonge M, Garralda E, Giannakis M, Smith DC, Dobson JR, McLaughlin ME, Seroutou A, Ji Y, Morawiak J, Moody SE, Janku F. Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours. Br J Cancer. 2021 Jul;125(1):28-37. doi: 10.1038/s41416-021-01389-8. Epub 2021 May 3.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: June 1, 2021): 185
• Original Estimated Enrollment (submitted: May 9, 2011): 50
• Estimated Study Completion Date: June 18, 2024
• Actual Primary Completion Date: June 14, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Diagnosis of locally advanced or metastatic cancer that has progressed despite standard therapy or for which no effective standard therapy exists and histological confirmation of one of the following diseases indicated below:

Single Agent Dose escalation part:documented B-RAF mutant colorectal cancer or pancreatic adenocarcinoma. In addition, tumors of any histological origin with documented genetic alterations upstream in the Wnt signaling pathway are eligible with prior agreement with Novartis.

Single Agent Dose expansion part: documented B-RAF mutant colorectal cancer with documented RNF43 mutation and/or RSPO fusion or pancreatic adenocarcinoma with documented RNF43 mutation. In addition, patients with tumors of any histological origin with documented genetic alterations upstream in the Wnt signaling pathway (e.g. RNF43 or RSPO fusion) are eligible with prior agreement with Novartis

LGK974 with PDR001: Dose escalation: patients with the following cancers that were previously treated with anti-PD-1 therapy and whose best response on that therapy was progressive disease (i.e. primary refractory): melanoma, lung SCC, HNSCC. Patients with esophageal SCC, cervical SCC or TNBC who are either naïve or primary refractory to prior anti-PD-1 therapy.

LGK974 with PDR001: Dose expansion: patients with:

• cutaneous melanoma that was primary refractory to prior anti-PD-1 therapy, defined as a best response of progressive disease or stable disease for <= 4 months, or disease recurrence with the first 6 months of adjuvant therapy. Patients with BRAF V600-mutant melanoma must have also received and been failed by prior systemic therapy with BRAF V600 inhibitor, with or without a MEK inhibitor.
• Cutaneous melanoma with acquired resistance to prior anti-PD-1 therapy, defined as progressive disease following response (PR or CR) or following stable disease for > 4 months. Patients with BRAF V600-mutant melanoma must have also received and been failed by prior systemic therapy with a BRAF V600 inhibitor, with or without a MEK inhibitor.

Exclusion Criteria:

• Impaired cardiac function
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of LGK974 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
• Brain metastases that have not been adequately treated
• Malignant disease other than that being treated in this study
• Laboratory abnormalities as specified in the protocol
• Osteoporosis, osteopenia
• Bone fractures within the past year
• Pathologic bone fracture
• Active, known or suspected autoimmune disease or severe hypersensitivity reactions to other monoclonal antibodies

Other protocol-defined inclusion/exclusion criteria may apply

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, France, Germany, Italy, Netherlands, Spain, United States

Administrative Information

• NCT Number: NCT01351103
• Other Study ID Numbers: CLGK974X2101; 2011-000495-33 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: External Affairs, Novartis Pharmaceuticals
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: March 2024